Atherosclerotic cardiovascular disease remains the leading cause of mortality in the United States (see, e.g., American Heart Association, 1999 Heart And Stroke Statistical Update, Dallas, Tex., American Heart Association). Gene therapy is a rapidly expanding field with great potential for the treatment of atherosclerotic cardiovascular diseases as well as diseases involving other organs or parts of a mammalian body (e.g., human body) in which therapeutic agents can be delivered to a targeted site of a vessel lumen. Several genes, such as vascular endothelial growth factor (VEGF), have been shown to be useful for preventing acute thrombosis, blocking post-angioplasty restenosis, and stimulating growth of new blood vessels (angiogenesis) (Nabel, 1995, Circulation 91: 541-548; Isner, 1999, Hosp. Pract. 34: 69-74).
In the early days of vascular gene therapy, many investigators were searching for the ideal vector, one that would allow efficient transduction and long-term stable transgene expression in target cells, including: (i) viral vectors, such as retroviral (Miller A. Retroviral vectors. Curr Top Microbiol Immunol 1992; 158:1-24), adenoviral (Kozarsky K, Wilson J. Gene therapy: adenovirus vectors (Review). Curr Opin genet Dev 1993; 3:499-503), and adeno-associated viral vectors (Muzyczka N. Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 1992; 158:97-129); and (ii) nonviral vectors, such as DNA and RNA vectors (Wolff J, Maline R, Williams P. Direct gene transfer into mouse muscle in vivo. Science 1990; 247:1465-1468), synthetic oligonucleotides (Stein C, Cheng Y. Antisense oligonucleotides as therapeutic agents—is the bullet really magical? Science 1993; 261:1004-1012), and liposomes (Felgner P, Gadek T, Holm M. Lipofection: A highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 1987; 84:7413-7417). None of these types of vectors, however, were found to be ideal for both efficient gene transfection and stable gene expression. For example, plasmid DNA has a number of advantages as a gene therapy vector, including (a) easy construction, (b) no need for an infectious agent, (c) long-term transgene expression, and (d) no immune responses. Plasmid DNA, however, suffers a prominent disadvantage because of the relatively low efficiency of transduction in vivo.
Another challenge to vascular gene therapy is the ability to deliver therapeutic genes to the target site. Different gene delivery techniques have been developed, including: ex vivo gene delivery, such as endovascular stents seeded with genetically modified endothelial cells which are then reimplanted into the target vessel, surgically-based delivery, which involves directly injecting genes into surgically-isolated target vessels; percutaneous delivery, which involves the direct administration of genes into the target through a percutaneous approach; and catheter-based delivery (Thomas J, Kuo M, Chawla M, et al. Vascular gene therapy. RadioGraphics 1998; 18:1373-1394). Of these gene delivery techniques, catheter-based delivery seems to hold the most promise for vascular applications.
Catheter-based gene delivery has some prominent advantages over other gene delivery methods, including (a) precise gene delivery to a specific anatomic location, (b) minimal morbidity, (c) no unwanted systemic effects, and (d) the ability to combine with conventional interventions, such as angioplasty and endovascular stent placement. Since 1990, several catheters have been tested as vector delivery systems, including double-balloon catheters [Goldman, Atherosclerosis #154], porous and microporous infusion catheters (Wolinsky H, Thung S. Use of a perforated balloon catheter to deliver concentrated heparin into the wall of the normal canine artery. J Am Coll Cardiol 1990; 15:475-481), hydrogel catheters (Fram D, Aretz T, Azrin M. Localized intramural drug delivery during balloon angioplasty using hydrogel-coated balloons and pressure-augmented diffusion. J Am Coll Cardiol 1994; 23:1570-1577), and dispatch catheters (Tahlil O, Brami M, Feldman L, Branellec D, Steg P. The Dispatch catheter as a delivery tool for arterial gene transfer. Cardiovasc Res 1997; 33:181-187). However, gene transfer with these delivery catheters is currently performed under x-ray fluoroscopy, which displays, using a contrast medium, only the lumen of the vessel without providing direct imaging information about the vessel wall or atherosclerotic plaques. Therefore, one cannot properly monitor either the interaction between the genes and the atherosclerotic lesion or the existence and the concentration of the genes in the target lesion during and after gene delivery.
As such, efficient gene transfection into a target-specific cell is one of the challenges for vascular gene therapy in cardiovascular disease. Several studies have shown that gene transfection and expression can be significantly enhanced one- to four-fold with heating, which has been tested in different cells, such as prostate tumor cells, chondrocytes, kidney cells, and arterial SMCs (Blackburn R, Galoforo S, Corry P, Lee Y. Adenoviral-mediated transfer of a heat-inducible double suicide gene into prostate carcinoma cells. Cancer Research 1998; 58:1358-1362; Greenleaf W, Bolander M, Sarkar G, Goldring M, Greenleaf J. Artificial cavitation nuclei significantly enhance acoustically induced cell transfection. Ultrasound in medicine & Biology 1998; 24:p587-595; Yang, et al. Unpublished data). Moreover, the incorporation of DNA with adjuvants or heat-sensitive promoters may further enhance gene transfection and expression under heating. Proposed mechanisms for heat-enhancement of gene transfection may include heating efforts that cause tissue fracture, increased permeability of the plasma membrane and cell metabolism, and increase the activity of heat-sensitive heat shock proteins. In clinical practice, however, it is not feasible to heat the entire body to temperatures (e.g., increase bulk body temperature by 4 deg) that have been shown to enhance transfection and expression. As such, the challenge now faced is how to place an internal heating source within the body to generate heat only in a local heating region at the target site rather than through the entire body. In addition, the challenge also posed is to provide such local heating in a fashion so as to allow for in vivo monitoring of the target site and surrounding tissue and so as to be effective in enhancing the delivery/administering of the gene for therapy.
It thus would be desirable to provide a new device, systems and methods for localized heating of a target site of a vessel, such as for example, the endothelial tissues of a blood vessel to facilitate the administration or delivery of a therapeutic medium to the target site. It would be particularly desirable to provide such a device, system and method that also would allow for MR/NMR imaging of the tissues at, about and proximal the target site while administering or delivering the therapeutic medium to the target site and while locally heating the tissues of the target site. It also would be particularly desirable to provide such devices, systems and methods that can allow a flow of fluid to be maintained within the vessel while performing any of localized heating, administering/delivering the therapeutic medium and MR/NMR imaging of the tissues at and proximal the target site.